6-amino-5-methyleneaminopyrimidines



United States Patent 3,429,878 6-AMINO-S-METHYLENEAMINOPYRIMIDINES Irwin J. Pachter, Woodbury, N.Y., and Joseph Weinstock, Phoenixw'lle, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application June 29, 1962, Ser. No. 206,153, which is a continuation-in-part of application Ser. No. 142,541, Oct. 3, 1961. Divided and this application Jan. 31, 1967, Ser. No. 612,836

when:

R represents hydrogen, lower alkyl, phenyl, thienyl, carbamoyl, hydroxyl or preferably R represents hydrogen, lower alkyl, phenyl, thienyl or amino;

US, Cl, 260-240 4 Cl i R represents hydrogen or lower alkyl, the same or dif- Int. Cl. C07d 51/42; A611; 27/00; C09b 23/00 ferent, hydrogen is preferred;

R represents hydrogen or an organic moiety having a maximum of 12 carbon atoms, such as lower alkyl, ABSTRACT OF THE DISCLOSURE 15 halogenated lower alkyl such as trifiuoromethyl, cycloalkyl, 0:,13-10W6I alkenyl, u,;3-cycloalkenyl, phenyl-afi- 7-am1nopter1dmes, which are usef il as diuretic and lower alkenyl, ,BJOWer alkynyl, phenyl-ogB-lower hypotensive agents and as intermediates for dyestuifs or alkynyl, lower alkenylalkylene, cycloanienylalkylene as antifolic ac d compounds, are prepa d from phenyl-lower alkenylalkylene, lower alkynylalkylene, dramlnopynmidines by a process with Schrtf bases h n l-l w alkynylalkylene, pheny, thienyl, furyl, w pyrrolyl, pyrimidyl, pyridyl, quinolyl, thiazolyl, benzyl, methylaminopyrimldines and 7-am1no-dihydropteridlnes I phenethyl, thenyl or carbamoyl; as intermediates. The -thiazolylpteridines also have R 4 corresponds to R h R is hydrogen, lower alkyl, ut lity as central nervous system s t1mulants. The 2,4,6- halogenated lower alkyl, cycloalkyl, lower alkenyl 131111119'5'cyanomefliflylamIHPEYTImIdmeS wh1c h alkylene, cycloalkenylalkylene, phenyl-lower alkenyltermediates for 7-am1nopter1dmes also have dluretic acalkylene lower alkYnYlalkYlene, Pheny1 1ower a1kyny1 nvltyalkylene, phenyl, thienyl, furyl, pyrrolyl, pyrimidyl, pyridyl, quinolyl, thiazolyl, benzyl, phenethyl, thenyl -This application is a divisional of Ser. No. 206,153, or carbamoyl when R3 15 an ufi'lower alkenyl filed June 29, 1962, which is a continuation-in-part of afl'cycloalkenyl phenyl'afi'lower alkellyl afi'lower Ser. No. 142,541, filed Oct. 3, 1961, and now abandoned. alkynyl or phenyl'afi-lower alkynyl R4 15 lower alkyl This invention relates to a novel process for the prepi i afi'lower alkenyl or aration of 7-aminopteridine derivatives, to novel interp Ower a any respecflvely and mediates useful in said process and to new 7-aminopteri- R5 represerits hydrogen or alkali metal Such as Sodium dine derivatives prepared by said process. 5 or potassmm The 7-aminopteridine derivatives prepared by the Preferred compounds of Formulas I-V are as folprocess and through the intermediates which are objects lows: of this invention are valuable pharmacodynamic agents, R represents in particular they are useful as diuretic and hypotensive agents. Certain of these pteridine derivatives have been 40 described as potent diuretic agents in US. Patents 2,975,- 180 and 2,963,481. Certain of the 6-amino-5-cyano- R2 methylarninopyrimidines in particular the 2,4,6-triamino- R represents phenyl or amino; S-cyanomethylaminopyrimidines which are prepared by R represents hydrogen or methyl; and the process of this invention and are intermediates in said R and R represent hydrogen, methyl, phenyl, thienyl, process for the preparation of 7-aminopteridines have pyrrolyl or carbamoyl. diuretic activity in their own right. The end products also The aryl moieties of R R and R; such as the phenyl have valuable utility as intermediates for preparing other moiety are, optionally, inertly substituted, that is suborganic compounds having utility as dyestuffs or as antistituted by moieties which are not reactive under the folic acid compounds. In addition the fi-thiazolylpteridine conditions of the process of this invention. Exemplary end products have utility as central nervous system of inert substituents are lower alkyl, lower alkoxy, stimulants. halogen and trifluoromethyl.

The process of this invention for the preparation of The terms lower alkyl, lower alkenyl, lower 7-aminopteridines is schematically represented as follows: alkynyl, alkylene and lower alkoxy" where used Formula I Formula II Formula 111 HN -R HN R HN -R 2 1 mono 2 1 R5CN 2 1 I l HZN N C=N N ON N l E l R -(JHN l R R R Formula V Formula IV HZN R1 HZN /N\/N\ R1 H l N R4 RI l N H R H R herein and in the claims denote moieties having from 16, preferably 1-3, carbon atoms. The term halogenated lower alkyl denotes moieties having 1-6, preferably 1-3, carbon atoms substituted by a halo moiety such as chloro, bromo or fiuoro. The terms cycloalkyl and cycloalkenyl denote moieties having -6 carbon atoms.

The pteridine products of Formula V which are objects of this invention could not be prepared by prior art procedures but are now available due to this invention. These compounds have the following formula:

N HzNI l N R4 in which:

R represents hydrogen, lower alkyl, phenyl, thienyl, carbamoyl, hydroxyl or R represents hydrogen, lower alkyl, phenyl, thienyl or amino;

R represents hydrogen or lower alkyl, the same or different;

R represents halogenated lower alkyl, and especially unsaturated alkyl or aralkyl moieties such as 0:,fl-IOW6I alkenyl, pheny 00,5 lower alkenyl, lower alkenylalkylene, cycloalkenylalkylene, phenyl-lower alkyenylalkylene, lower alkynylalkylene or phenyl-lower alkynyl-alkylene.

Also included in this invention are the nontoxic pharmaceutically acceptable, acid addition salts of the above pteridines. These salts are prepared by reacting the base in an organic solvent such as ethyl ether, ethyl acetate or a lower alkanol with an excess of the acid. Exemplary of suitable acids are hydrochloric, acetic, hydrobromic, sulfuric, phosphoric, sulfamic, ethanedisulfonic, maleic, citric, etc. acids.

The novel Schiff base and 6-amino-5-cyanomethylaminopyrimidine intermediates of Formulas II and III, respectively, are also objects of this invention. The acid addition salts of these compounds are further objects of this invention. Such salts are prepared by reacting the bases with an organic or inorganic acid in a lower alkanol such as ethanol, methanol or isopropanol with isolation of the salt by cooling and filtering. Exemplary of such salts are those prepared with maleic, citric, acetic, hydrochloric or hydrobromic acids.

The 7-amino-5,G-dihydropteridines of Formula IV are intermediates in the preparation of the diuretic pteridines of Formula V. The position of the double bond in the pyrazine ring of the dihydropteridine nucleus is at present not definitely known. The compounds have been designated herein in most instances as 5,6-dihydropteridines, however, the compounds may equally well be 5,8-dihydropteridines. Particularly where R, is an aryl moiety, the product is likely to be the 5,8-dihydropteridine which would provide conjugation of the double bond with the aryl moiety, R

It is apparent that the compound of Formula IV in which R is an a, 8-unsaturated moiety will readily shift a double bond to form the pteridine compounds of Formula V. Therefore the cafl-alkenyl and -alkynyl compounds of Formula IV will isomerize to producealkyl and 01, 8- alkenyl pteridines, respectively, of Formula V.

The compounds of Formula IV in which the R moiety contains an unconjugated unsaturated bond are designated as lower alkenylalkylene, cycloalkenylalkylene, phenyl-lower alkenylalkylene, lower alkynylalkylene and phenyl-lower alkynylalkylene to distinguish them from the O B-unsaturated moieties. The distinction between the a,;8-unsaturated moieties and other unsaturated groups in the process of this invention is the ability of the former to isomerize to give the pteridine products, while the latter must undergo the additional step of oxidation of the dihydropteridines to form the pteridines of Formula V.

Also included in this invention are the process and intermediates as described above in which the N-atoms of the pyrazine ring of the dihydropteridines of Formula IV are substituted by lower alkyl or aralkyl moieties such as benzyl or phenethyl. Dihydropteridines which contain a substitutent in the 8 position are prepared as by-products of the cyclization of a 4-monoalkylamino-5-cyanomethylaminopyrimidine. S-substituted-dihydropteridines are prepared by reduction of the Schiif bases of Formula II followed by reaction of the resulting 5-alkylaminopyrimidine with R CHO and R CN to give the intermediate 5-(alkylcyanomethylamino) pyrimidine which is then cyclized to the S-alkyldihydropteridine.

The process of this invention is most conveniently carried out without isolating the Schifl base intermediates of Formula II. The preparation of the S-cyanomethylaminopyrimidines of Formula III is then accomplished in one step as follows:

Formula I Formula III N N HEN R1 HzN "'RX l I HZN N RaCIJHN N The terms R, R and R are as defined hereabove.

The starting materials for the process of this invention, namely the 5,6-diaminopyrimidines of Formula I, are either known to the art or are prepared by standard procedures such as by reduction of the corresponding 5- nitroso compounds disclosed in U.S. Patent 2,975,180. The 6-amino-5-nitrosopyrimidines are reduced to the 5,6- diaminopyrimidine starting materials of Formula I by means of chemical reducing agents or by catalytic hydrogenation.

According to the process of this invention the 5,6-diaminopyrimidine of Formula I is reacted with at least one molar equivalent of the carbonyl compound having the formula R CHO in which R is as defined hereabove in an inert solvent in which the reactants are substantially soluble preferably in a lower alkanol such as ethanol or methanol. The reaction mixture is preferably heated, such as on a steam bath, at about 4590 C. for about 3-15 minutes. The Schilf base of Formula H is formed and is optionally isolated by concentrating the mixture, filtering and recrystallizing the solid product from a suitable solvent such as a lower alkanol, for example ethanol or isopropanol.

The Schiif base of Formula II is reacted vw'th R CN in which R is an alkali metal such as sodium or potassium or is, preferably, hydrogen together with an acid such as a dilute mineral acid for example hydrochloric, sulfuric or phosphoric acids or preferably, a lower alkanoic acid such as acetic acid. A lower alkanol solvent such as ethanol or methanol is advantageously added to the reaction mixture. The reaction is preferably carried out at elevated temperature, advantageously at about 45-90 C. for about 5-30 minutes. The 6-amino-5-cyanomethylaminopyrimidine of Formula III is isolated from the reaction mixture by cooling and filtering.

The S-cyanomethylaminopyrimidine can be formed directly by the reaction of the 5,6-diaminopyrimidines of Formula I with a carbonyl compound, i.e. R CHO, a cyanide compound, i.e. R CN, and an acid such as mineral acid or a lower alkanoic acid at about 45 C. to about C. for about 5-30 minutes, R and R being as defined hereabove.

The 6-amino-S-cyanomethylaminopyrimidine intermediate of Formula III is treated with an alkali metal lower alkoxide, such as sodium or potassium methoxide or ethoxide, or an alkali metal cyanide such as sodium or potassium cyanide in a lower alkanol solution such as methanol or ethanol solution. The reaction is preferably carried out at elevated temperatures such as at about 45-85 C., conveniently at the reflux temperature of the reaction mixture. The reaction is usually allowed to proceed for about 5-10 minutes. The mixture is concentrated in vacuo to give the intermediate crude 7-amino- 5,6-dihydropteridine of Formula IV. The dihydropteridines of Formula IV in which R is an a d-unsaturated moiety rearrange directly to the pteridines of Formula V. Other dihydropteridines are converted to the pteridines by oxidation. The dihydro compound is air oxidized by heating in an inert solvent having a boiling point of about 150-265 C., such as phenyl ether or dimethylformamide, conveniently at the reflux temperature of the solvent and the pteridine product is isolated by cooling and filtering. Alternatively, the dihydropteridine is converted to the pteridine by treating with an oxidizing agent such as potassium ferricyanide, potassium permanganate or, conveniently, aqueous hydrogen peroxide.

Alternatively, the cyanomethylaminopyrimidine intermediates of Formula 111 are prepared as follows:

and X is a reactive halogen such as bromo, chloro or iodo.

The 5,6-diaminopyrimidine is reacted with an acetonitrile derivative, i.e. a-X-acetonitrile, in which X is as defined above, in a lower alkanol solvent such as ethanol or methanol. Advantageously, an acid binding agent such as sodium or potassium carbonate is present in the reaction mixture. The reaction is carried out at elevated temperature, conveniently at reflux temperature of the reaction mixture, for a period of about 1060 minutes.

The following terms as used herein and in the claims are thus defined:

Lower alkanola straight or branched chain aliphatic alcohol having 1-6, preferably l-3, carbon atoms.

Lower alkanoic acida fatty acid having 2-4, preferably 2-3, carbon atoms.

Lower alkoxide-an alkoxide moiety having 1-6, preferably 1-3, carbon atoms.

Reaction conditions other than those described are operative but without particular advantage over those described hereabove. The following examples will illustrate the novel process and intermediates of this invention and will serve to make them fully apparent to one skilled in the art. These examples are not to be construed as limiting the operability of this invention but, on the contrary, are indicative of its wide scope of usefulness.

EXAMPLE 1 A mixture of 5.0 g. of 2,4,5,6-tetra-aminopyrimidine hydrochloride, 6.0 g. of benzaldehyde and 10 ml. of acetic acid is heated on a steam bath until solution is achieved. Hot absolute ethanol (75 ml.) is added and the mixture is heated to boiling. A stream of hydrogen cyanide gas is passed into the solution for about ten minutes during which the temperature falls to 65 C. The reaction mixture is allowed to stand at room temperature for five hours, then is filtered to give 2,4,6-tri- 6 amino-S-(a-cyanobenzylamino)pyrimidine hydrochloride, M.P. 197 C. (dec.).

Five grams of 2,4,6-triamino-5-(a-cyanobenzylamino)- pyrimidine hydrochloride, 2.5 g. of sodium methoxide and 40 ml. of methanol are heated at reflux for ten minutes. The mixture is cooled and filtered. The solid material obtained is refluxed for five minutes with 40 ml. of phenyl ether to give, on cooling and filtering, 2,4,7-triamino-G-phenylpteridine.

EXAMPLE 2 A mixture of 15.0 g. of 2,4,5,6-tetra-aminopyrimidine, 15.0 g. of benzaldehyde and 30 ml. of acetic acid is heated to obtain a solution. To this solution is added 300 ml. of hot 95% ethanol and 15.0 of potassium cyanide. The mixture is refluxed for five minutes, then allowed to stand for three hours and filtered to give 2,4,6-triamino-5-(a-cyano-benzylamino pyrimidine acetate which is recrystallized from ethyl acetate, M.P. 162- 164 C. (dec.).

A 5.0 g. sample of 2,4,6-triamino-5-(a-cyanobenzylamino)pyrimidine acetate and 2.5 g. of sodium methoxide are added to 40 m1. of methanol. The mixture is refluxed for ten minutes and then is allowed to stand for eight hours. The resulting solid material is filtered oif, then refluxed in phenyl ether solution for five minutes. Cooling and filtering gives 2,4,7-triamino-6-phenylpteridine.

EXAMPLE 3 A solution of 10.0 g. of 4,5,6-triamino-2-phenylpyrimidine in 75 ml. of methanol and 25 ml. of acetic acid is treated with 5.0 g. of sodium cyanide in 25 ml. of water and 10 g. of benzaldehyde in 20 ml. of methanol. The mixture is allowed to stand at room temperature for about 16 hours. The precipitate which forms is filtered off to give 4,6-diamino-5-(a-cyanobenzylamino)-2-phenylpyrimidine which is recrystallized from dimethylformamide-methanol to give yellow plates, M.P. 20l-203 C.

A 5.0 g. sample of 4,6-diamino-5-(a-cyanobenzylamino)-2-phenylpyrimidine, 5.0 g. of sodium methoxide and ml. of methanol are heated at reflux for 10 minutes. To the hot solution is added 80 ml. of water and 10 ml. of 30% hydrogen peroxide. The mixture is allowed to stand at room temperature for five hours. Filtration and recrystallization from methanol gives 4,7-diamino-2,6-di phenylpteridine.

EXAMPLE 4 Ten grams of 2,4,5,G-tetra-aminopyrimidine, 12.0 g. of benzaldehyde and 35 ml. of ethanol are heated on a steam bath for five minutes. Cooling and filtering gives 2,4,6-triamino-5 benzylideneaminopyrimidine. This Schitf base may be converted to its hydrochloride salt by heating with ethanolic hydrogen chloride, then cooling and filtering.

The Schitf base prepared above is dissolved in acetic acid. Hot ethanol is added. The resulting mixture is heated to the boiling point and treated with a stream of hydrogen cyanide gas. Working up as in Example 1 gives 2,4,6-triamino-5-(a-cyanobenzylamino)pyrimidine.

Refluxing 7.5 g. of the above prepared cyano compound with 4.2 g. of sodium ethoxide and 60 ml. of ethanol for eight minutes, then cooling, concentrating and refluxing the residue in phenyl ether for five minutes gives, upon cooling and filtering, 2,4,7-triamino-6-phenylpteridine.

EXAMPLE 5 A mixture of 10.6 g. of p-chlorobenzaldehyde, 19.0 g. of phenylsulfonyl chloride and 9.0 g. of potassium cyanide in 300 ml. of ethanol is heated on a steam bath for one hour. Cooling, concentrating and filtering gives p-chlorou-cyanobenzyl phenylsulfonate.

Treating 14.0 g. of 2,4,5,6-tetra-aminopyrimidine with the above prepared p-chloro-u-cyanobenzyl phenylsulfonate in ethanol solution containing sodium carbonate at reflux temperature for 15 minutes, gives, after cooling and filtering, 2,4,6-triamino--(p-chloro-a-cyanobenzylamino) pyrimidine. In the manner of Example 2 this pyrimidine is converted to 2,4,7-triamino-6-(p-chlorophenyl) pteridine.

EXAMPLE 6 EXAMPLE 7 By the method of Example 4 using as starting materials in equimolar amounts in place of benzaldehyde:

formaldehyde acetaldehyde 3-chloropropionaldehyde propargyl aldehyde cyclohexanecarboxaldehyde Z-quinolinecarboxaldehyde Z-furaldehyde 3-phenylpropionaldehyde 5-pyrimidinecarboxaldehyde the following compounds are prepared:

2,4,7-triaminopteridine 2,4,7-triamino-6-methylpteridine 2,4,7-triamino-6- (2-chloroethyl) pteridine 2,4,7-triamino-6-vinylpteridine 2,4,7-triamino-6-cyclohexylpteridine 2,4,7-triamino-6- (Z-quinolyl) pteridine 2,4,7-triamino-6-(2-furyl pteridine 2,4,7-triamino-6-phenethylpteridine 2,4,7-triamino-6-(5-pyrimidyl)pteridine and the corressponding dihydropteridines.

EXAMPLE 8 When the following compounds are used as starting materials in equimolar amounts in place of benzaldehyde in Example 4.

4-thiazolecarboxaldehyde Z-thiazolecarboxaldehyde S-thiazolecarboxaldehyde Z-thiopheneacetaldehyde 2-pyridinecarb oxaldehyde the products obtained are respectively:

2,4,7-triamino-6- (4-thiazolyl pteridine 2,4,7-triamino-6- (2-thiazolyl) pteridine 2,4,7-triamino-6- (S-thiazolyl pteridine 2,4,7-triami11o-6- 2-thenyl) pteridine 2,4,7 -triamino-6 (2-pyridyl pteridine.

EXAMPLE 9 Following the method of Example 4, 10.0 g. of 4,5,6- triamino-2-phenylpyrimidine and 5.0 g. of glyoxylamide are reacted. Upon completion of the steps outlined in Example 4, the intermediate 4,7 diamino 5,6-dihydro-2- phenyl 6 pteridinecarboxamide is converted to 4,7-diamino-2-phenyl-6-pteridinecarboxamide.

Similarly using 10.0 g. of 4,5,6-triamino-2-(Z-thienyl) pyrimidine, prepared by reduction of 4,6-diamino-5- nitroso-2-(2-thienyl) pyrimidine, and 5.0 g. of glyoxylamide in the procedure of Example 4, there is obtained 4.7-diamino-2 (Z-thienyl) -6-pteridinec arboxamide.

In the same manner, 5,6-diamino-4-methylamino-2- phenylpyrimidine and 5,6-diamino 4 dimethylamino-Z- phenylpyrimidine, prepared by reduction of the corresponding S-nitrosopyrim'idines, are reacted with glyoxylamide to give 7-amino-4methylamino-2-phenyl-6-pteri dinecarboxamide and 7-amino-4-dimethylamino-2-p'henyl- 6-pteridinecarboxamide, respectively.

EXAMPLE 10 Reacting 15 m1. of formaldehyde with 4.0 g. of 4,5,6- triaminopy'rimidine by the procedure of Example 4 gives, as the final product, 4,7-diaminopteridine.

Similarly substituting benzaldehyde in place of formaldehyde yields 4,7-diamino-6-phenylpteridine.

EXAMPLE 1 1 Ten grams of 2,4,5 ,6-tetra-aminopyrimidine and 7.5 g. of Z-thiophenecarboxaldehyde are heated in ethanol solution for five minutes at 90-95 C. to give 2,4,6-triamino- 5- (Z-thienyhnethyleneamino) pyrimidine.

A stream of hydrogen cyanide gas is passed into a dilute solution of hydrochloric acid in ethanol containing the above prepared pyrimidine to give, after cooling and filtering, 2,4,6-triamino 5 (a-cyano 2 thienylmethylamino)pyrimidine. This cyano com-pound is refluxed with 3.0 g. of sodium cyanide in ethanol for five minutes to give the intermediate 2,4,7-triamino-5,8-dihydr0-6-(2- thienyl)pteridine which is refluxed with phenyl ether for five minutes to give 2,4,7-triamino-6- (2-thienyl)pteridine.

In a similar manner using 7.5 g. of 3-thiophenecarboxaldehyde as the starting material, 2,4,7-triamino-6-(3- thienyl)pteridine is prepared.

EXAMPLE 12 A mixture of 10 g. of 2,4,5,6-tetra-aminopyrimidine, 14.0 g. of p-trifluoromethylbenzaldehyde and 20 ml. of acetic acid is heated. The resulting solid is taken up in 1200 ml. of boiling ethanol and hydrogen cyanide gas is passed into the solution for 2-5 minutes. The mixture is filtered and allowed to stand overnight. The precipitate is isolated by filtration to give 5-(u-cyano-4-trifluoro methylbenzylamino) 2,4,6 triaminopyrimidine hydrochloride which is dissolved in methanol and treated with excess sodium methoxide. The mixture is refluxed for ten minutes and diluted with 200 ml. of water and 10 ml. of 30% hydrogen peroxide. The resulting mixture is refluxed for ten minutes, then cooled and filtered to give 2,4,7 -triamino-6- (4-trifluoromethylphenyl) pteridine.

EXAMPLE 13 By the method of Example 4, 8.0 g. of 4,5,6-triamino- 2-methylpyrimidine and 5.0 g. of glyoxylamide are reacted to give 4,7-diamino-2-methyl-6-pteridinecarboxamide.

In the same manner 4,7-diamino-2-ethyl-6-pteridinecarboxamide is prepared from 4,5,6-triamino-2-ethylpyrimidine and glyoxylamide.

EXAMPLE 14 A mixture of 9.0 g. of 2,4,5,6-tetra-aminopyrimidine hydrochloride in 40 ml. of methanol and 25 ml. of acetic acid is heated at 50 C. and treated first with a solution of 5 g. of sodium cyanide in 17 m1. of water and then with a solution of 9.5 g. of 3-cyclohexene-l-carboxaldehyde in 10 ml. of methanol. The resulting mixture is kept at 20 C. overnight. Upon filtration there is obtained 2,4,6 triamino-S-(wcyano-3-cyclohexenylmethylamino) pyrimidine, M.P. 134l35 C.

Refluxing the above prepared cyano compound with 5.0 g. of sodium methoxide in 80 ml. of methanol for 10 minutes, adding ml. of water and 12 ml. of 30% hydrogen peroxide, allowing the resulting mixture to stand at room temperature, filtering and recrystallizing from methanol gives 2,4,7-triamino 6 (3-cyclohexenyl)pteridine, M.P. 350 C.

EXAMPLE 15 A mixture of 9 g. of 2,4,5,6-tetra-aminopyrimidine hydrochloride, 10 g. of cinnamaldehyde, g. of sodium cyanide in 95 ml. methanol and 60 ml. of acetic acid are reacted as in Example 14 to give 2,4,6-triamino-5-(acyanocinnamylamino)pyrimidine, M.P. 134136 C.

A 9.3 g. sample of 2,4,6-triamino-5-(a-cyanocinnamylamino)pyrimidine acetate (prepared by treating the free base with excess acetic acid, concentrating and filtering) is added to a solution of 9.0 g. of sodium methoxide in 200 ml. of methanol. The mixture is stirred and refluxed for two minutes. The precipitate was collected, washed with methanol, dried and recrystallized from ethanol to give 2,4,7-triamipo-6- 3-phenethylpteridine, M.P. 296- 298 C. (dec.).

EXAMPLE 16 A solution of 9 g. of 2,4,5,6-tetra-aminopyrimidine hydrochloride in 45 ml. methanol and 45 ml. acetic acid is treated with 5 g. of sodium cyanide in 20 ml. of Water and g. of phenylpropargylaldehyde in 10 ml. of methanol. The mixture is heated to 50 C., then cooled for three hours at 7 C. On filtering there is obtained 2,4,6- triamino-5-(a-cyano-'y-phenylpropargylamino)pyrimidine.

To a solution of 6.0 g. of sodium methoxide in 125 ml. of methanol is added 6.0 g. of 2,4,6-triamino-5-(a-cyano- 'y-phenylpropargylamino)pyrimidine. The mixture is refluxed for three minutes, then cooled and filtered. The solid product is recrystallized from ethanol to give 2,4,7- triamino-6-styrylpteridine, M.P. 345-347 C. (dec.).

One gram of 2,4,7-triamino-6-styrylpteridine is dissolved in dilute hydrochloric acid to give, on cooling and filtering, the hydrochloride salt.

EXAMPLE 17 A solution of 36 g. of 2,6-dichloro-S-nitro-4-pyrimidine carboxylic acid methyl ester in 720 ml. of 10% ammonia in methanol is heated in an autoclave at 100 C. for six hours. The mixture is allowed to stand overnight, then is evaporated and the residue is dissolved in dilute hydrochloric acid. Adding ammonia, filtering the precipitate and recrystallizing it from \dimethylformamide gives 2,6- diamino-4-carbamoyl-5-nitropyrimidine.

A mixture of 1.0 g. of 2,6-diamino-4-carbamoyl-5- nitropyrimidine, 200 ml. of methanol and /2 teaspoon of Raney nickel catalyst is hydrogenated. The resulting mixture is filtered and the alcohol is evaporated from the filtrate. The residue is recrystallized from water to give 2,5,6 triamino-4-carbamoylpyrimidine, M.P. 286- 288 C. (dec.).

A sample of 2,5,6-triamino-4-canbamoylpyrimidine in methanol and acetic acid is heated to 50 C. and treated with aqueous sodium cyanide and benzaldehyde in methanol to give 2,6-diamino-4-carbamoyl-5-(a-cyanobenzylamino) pyrimidine. Refiuxing this pyrimidine with sodium methoxide in methanol for 10 minutes, adding aqueous hydrogen peroxide to the solution and allowing it to stand at room temperature for five hours gives, after filtering and recrystallizing in methanol, 2,7-diamino-4-carbamoyl-6-phenylpteridine.

10 EXAMPLE 18 Five grams of 2,4,5,6-tetra-aminopyrimidine in methanol and acetic acid is heated to 50 C. and treated first with 3.5 g. of sodium cyanide in water and then with 5.8 5 g. of oz,oc,oz trifluoroacetaldehyde. Cooling and filtering gives 2,4,6-triamino-5-(m cyano 3,13,,6 trifluoroethylamino)pyrimidine which on refluxing with sodium ethoxide in ethanol, then cooling, concentrating and refluxing the residue with aqueous hydrogen peroxide gives 2,4,7- triamino-6-trifluoromethylpteridine.

This compound (500 mg.) is dissolved in hot dilute phosphoric acid. Cooling separates the phosphate salt.

EXAMPLE 19 By the procedure of Example 1, 10 g. of 2,5,6-triaminopyrimidine is reacted with slight excess of one molar equivalent of benzaldehyde in acetic acid and absolute ethanol. A stream of hydrogen peroxide gas is passed into the solution and after working up as in Example 1 there is obtained 2,6 diamino-5-(a-cyanobenzylamino) pyrimidine. Refluxing this pyrimidine with sodium meth oxide in methanol and treating the resulting dihydropteridine with hydrogen peroxide gives 2,7-diamino-6-phenylpteridine.

Similarly reacting molar equivalent amounts of 2,5,6- triamino-4methylpyrimidine and 2,5,6-triamino 4 pyrimidinol with benzaldehyde, refluxing the resulting cyano intermediate with sodium methoxide in methanol and oxidizing the intermediate dihydropteridine with hydrogen peroxide gives 2,7-diamino-4-methyl-6-phenylpteridine and 2,7-diamino-4-hydroxy 6 phenylpteridine, respectively.

EXAMPLE 20 2,5,6-triarnino-4-phenylpyrimidine is prepared as follows:

Known 2 amino 4 phenyl-6-hydroxypyrimidine is coupled with benzenediazonium chloride in aqueous solution at the 5-position. The 6 hydroxy compound is converted to a 6-chloro compound with phosphorous oxychloride then reacted with butanolic ammonia to form the 6-amine. The coupled diazonium moiety is then removed by catalytic reduction to give the desired triamino compound, M.P. 220-222 C.

A mixture of 20 g. of 2,5,6-triamino-4-phenylpyrimidine in methanolic acetic acid at 50 C. is treated with an aqueous solution of 6 g. of sodium cyanide then with a methanol solution of 7.5 g. of glyoxylamide. The resulting mixture is cooled and filtered to give 2,6-diamino- S-(a cyanocarbamoylmethylamino)-4-phenylpyrirnidine.

The above prepared cyano compound is refluxed with sodium methoxide in methanol then treated with aqueous hydrogen peroxide to give 2,7 diamino 4 phenyl 6- pteridine carboxamide.

What is claimed is:

1. A chemical compound of the class consisting of a free base and its acid addition salts, said free base having the following formula:

HzN a i C=N in which:

R is

Rs R2 hydrogen and lower alkyl and 11 a 112 R is a member selected from the group consisting of References Cited hydrogen, lower alkyl, halogenated lower alkyl, UNITED STATES PATENTS cycloalkyl, mi-lower alkenyl, a,,8-cycloalkenyl, phen- YLDMSJOWer alkenyl a,l3 10wer alkynyl, 1 2,285,260 6/1942 Downing Et al. 260-256.4 XR

lower alkynyl, lower alkenylalkylene, cycloalke- 5 2,487,569 11/1949 Mackey 260256-4 XR nylalkylene, phenyl-lower alkenylalkylene, lower 211- OT REFERENCES kynylaikylene phenyl'bwer alkynylallylsne l Fidler et 211.: J. Chem. Soc. 1957, pp. 3980 to 3984. Y th1e11y1, y PY Y PY YL Pyfldyl, Beilsteins Handbuch der Organischen Chemie, vol. 24 qumolyl thlazolyl benzyl phenethyl thenyl and (4th ed.), system No. 3774, p. 495, Verlag Julius carbamoyl. 10 Springer, Berlin, Germany (1936).

2. A chemical compound according to claim 1 m whlch Traube et at Ben Dem Chem VOL 39, 227 to R and R are amino and R is phenyl. 229 and 232 1906 3. A chemical compound according to claim 1 in which R and R1 are amino and R3 is thienyL JOHN D. RANDOLPH, Przmary Examiner.

4. A chemical compound according to claim 1 in which 15 R and R are amino and R is N-methylpyrrolyl. 260141, 251.5, 256.4, 256.5; 424250, 251 

